Survival and neurological outcome after sudden cardiac arrest (CA) remain very poor. Our prior work focused on understanding the return of neuro-electrical activity after CA and led to the discovery of a) quantitative signal processing methods that track brain injury and recovery after CA, b) recovery of thalamocortical networks during restitution of arousal after CA and c) the patterns of electrical rhythms and time course when therapy may impact recovery. Recent clinical reports demonstrate compelling therapeutic benefits of hypothermia following CA and a better understanding of the role of the thalamus in chronic disorders of consciousness after CA. Our proposal harnesses these opportunities to uncover the acute neurophysiologic mechanisms of arousal post-CA to develop clinically applicable diagnostic methods and optimize therapeutic hypothermia delivery. The specific aims of this project are: Aim 1: We will discover the clinically relevant and neurophysiologically validated electrical markers of arousal from coma after CA. We will test the hypotheses that a) coma is marked by abnormal coupling of thalamic and cortical potentials, b) quantitative analysis of cortical somatosensory evoked potentials (SSEP) will track recovery of normal thalamocortical coupling, and c) entropy-based quantitative EEG (qEEG) analysis will capture sequential changes in thalamocortical coupling during recovery from CA injury. Aim 2: We will study the mechanism by which induced hypothermia results in enhanced neurophysiologic recovery. We will test the hypotheses that a) multi-unit (MU) recording from thalamus and cortex will demonstrate accelerated normalization of thalamocortical coupling with induced hypothermia, b) hypothermia accelerates normalization of SSEP indicating restoration of the subcortical pathway, and c) normalization of qEEG signals recovery of cortical function. Aim 3: Most advances in hypothermia are blindly directed toward faster cooling, without objective indicators of the brain's response to temperature. We will test the hypothesis that the depth and duration of hypothermia can be objectively titrated to non-invasive qEEG and SSEP markers of thalamocortical coupling in order to maximize brain recovery. This multifaceted approach - starting with direct multiunit recordings of thalamocortical components of the arousal system followed by non-invasive evoked potential and EEG monitoring - will allow for the comprehensive development of real-time neurophysiologic tools to titrate hypothermia treatment. The first phase of our basic research has already spawned an NIH-sponsored Phase IIB multi-center clinical trial. Our quantitative, neuroelectrophysiology-guided optimization of hypothermia delivery should be similarly applicable to monitoring patients and guiding induced hypothermia clinical trials in the near future.